Individuals who self-administer stimulant drugs repeatedly at closely spaced intervals can develop psychoses. Attempts to understand athe neurobiology of psychoses by mimicking this pattern of stimulant treatment in experimental animals have been few in number and have not employed recently developed neurochemical, immunologic, or molecular neurobiologic techniques. Experiments performed in this laboratory have suggested that repeated administration of methamphetamine to rats has consequences for striatal dopaminergic terminal overflow that differ from those of acute administration of this drug. Further experiments have revealed that Fos, the protein product of the proto-oncogene, c-fos, has a qualitatively different localization in brain regions of rats undergoing repeated versus acute methamphetamine treatments. Of particular interest is the finding that rats given repeated methamphetamine treatments displayed increased numbers of Fos=immunoreactive nuclei in two interconnected limbic cortical regions (postsubiculum and retrosplenial cortex), the anterodorsal thalamic nucleus (which innervates both these limbic cortices) and in paraventricular thalamic nucleus (which innervates subiculum and prelimbic cortex). This proposal is designed (i) to characterize alterations in Fos immunoreactivity during a course of chronic methamphetamine administration to rats, and (ii) to begin studying how the limbic cortex and anterodorsal and paraventricular thalamic nuclei become activated during chronic methamphetamine treatment. The specific aims of this proposal include: (i) development of a chronic methamphetamine regimen in rats what minimizes injury to monoaminergic neurons, (ii) characterization of the pattern of brain Fos immunoreactivity in rats exposed to this chronic treatment regimen, (iii) comparison between the brain Fos immunoreactivity of rats exposed acutely to NMDA antagonists (phencyclidine, MK-801) versus chronically to methamphetamine, (iv) characterization of the effects of chronic methamphetamine or acute NMDA antagonist administration on the induction of the heat shock protein, HSP72, in these same brain regions, (v) assessment of time-dependent alterations in the dopamine overflow occurring in limbic cortex during the regimen of chronic methamphetamine administration, (vi) determination of the effects of injury to specific dopamine terminal fields ont he methamphetamine- or NMDA antagonist-induced pattern of Fos immunoreactivity, and (vii) identification of populations of Fos-immunoreactive neurons in chronic methamphetamine-treated animals, based on their axonal projections.